Study of zidovudine addition in HIV-associated neurocognitive disorders

齐多夫定加用治疗 HIV 相关神经认知障碍的研究

• 批准号: 8676942
• 负责人: Albert Anderson
• 金额: $ 17.99万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-10 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8676942
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Anti-Retroviral Agents; Area; Award; Basic Science; Biological Markers; Biometry; Brain; Caring; Cerebrospinal Fluid; Chronic; Clinical Research; Clinical Trials; Cognitive; Dementia; Development; Diagnosis; Disease; Future; Generic Drugs; Goals; Gold; Grant; HIV; HIV diagnosis; HIV encephalitis; Highly Active Antiretroviral Therapy; Immune system; Impairment; Incidence; Individual; Insurance; Interdisciplinary Study; Interferon-alpha; Interferons; International; Knowledge; Lead; Lymphocyte Activation; Master' s Degree; Medical; Mentors; Mission; Modeling; Modification; Morbidity - disease rate; National Institute of Mental Health; Neuraxis; Neurocognition; Neurocognitive; Neuropathogenesis; Neuropsychological Tests; Neuropsychology; Neurosciences; Pathogenesis; Patients; Performance; Peripheral; Pharmaceutical Preparations; Placebos; Poverty; Prevalence; Principal Investigator; Public Health; Publishing; Quality of life; Randomized; Regimen; Research; Research Design; Research Personnel; Research Proposals; Residual state; Resources; Risk; Risk Factors; Role; Sampling; Severities; Short-Term Memory; Site-Directed Mutagenesis; Source; Specimen; Standardization; T-Lymphocyte; Testing; Therapeutic Intervention; Therapeutic Studies; Time; Translational Research; Unemployment; United States; Viral; Virus Diseases; Work; Zidovudine; antiretroviral therapy; base; career development; clinical care; clinically significant; cytokine; diagnosis standard; disability; experience; hazard; health related quality of life; health science research; immune activation; improved; meetings; member; mild cognitive impairment; monocyte; mortality; mouse model; neuropsychological; novel therapeutic intervention; public health relevance; repository; research and development; responsible research conduct; standard of care; systems research; validation studies; virus pathogenesis

DESCRIPTION (provided by applicant): This proposed K-23 grant resubmission will provide for the career development of a junior principal investigator who aims to become a leader in human immunodeficiency virus (HIV) clinical research with a focus on the central nervous system (CNS) involvement of HIV. The CNS complications of HIV continue to be a major source of morbidity and mortality. The prevalence of HIV-associated neurocognitive disorder (HAND) is increasing. The presence of HAND is a risk factor for work disability, poor quality of life, and mortality. The proposed research plan addresses three of the most important areas of HIV central nervous system (CNS) research: the possibility that certain antiretroviral medications differentially affect cognitive improvement in HAND, the role of specific cerebrospinal fluid (CSF) biomarkers as indicators of HAND activity, and the incompletely defined role of monocyte and lymphocyte activation in HIV neuropathogenesis. The proposed research is highly relevant to NIMH missions, which include the development of novel therapeutic approaches to mitigate the CNS complications of HIV. The research will take place in an urban HIV center where many of the patients have limited resources due to poverty and lack of medical insurance. Zidovudine is an antiretroviral medication that is now in generic form in the United States, is among the most effective antiretrovirals in penetrating the CNS, and is historically the best studied antiretrovirl for HIV-associated dementia. The investigator's primary hypothesis is that the addition of zidovudine in antiretroviral-na¿ve subjects with HAND will result in significantly greater neurocognitive improvement and biomarkers over the course of 48 weeks. This will be tested in a small clinical study in which subjects will receive a standard of care antiretroviral regimen plu either zidovudine or placebo. If the study shows superior improvement in neurocognition and/or biomarkers for subjects randomized to zidovudine, the team will pursue larger studies of zidovudine addition for individuals with HAND. The secondary aims of the proposal pertain to the hypothesis that biomarkers are a reflection of HAND and that cytokines and peripheral immune activation independently contribute to HAND and may be targets for modification with future therapies. The research team aims to estimate normal CSF biomarker values based on an established large repository of samples. They have shown that certain biomarkers correlate with HAND severity and improve during treatment. One aim would be to test a composite score of eight biomarkers alongside standardized neuropsychological testing. If a promising correlation is demonstrated, the biomarker score would be tested in larger studies as a correlate of HAND. The research team has also demonstrated in previous work that CSF IFN-alpha levels inversely correlate with neuropsychological scores in subjects with HAND. They have also shown that in a mouse model of HIV encephalitis, treatment with IFN-alpha blockade was associated with a benefit in working memory and decreased pathological markers in the brain. The proposed clinical study will allow the team to build on these findings. The team hypothesizes that individuals with residual neurocognitive impairment despite effective antiretroviral therapy will have higher residual CSF IFN-alpha levels. This would form the basis for clinical studies of IFN-alpha modifying therapy that the research team has developed for individuals with HAND. Another secondary aim is to examine the role of peripheral monocyte and lymphocyte activation in HAND. It is clear that peripheral lymphocyte activation contributes to overall AIDS pathogenesis. However, it is not known if lymphocyte activation independently contributes to HAND. Current evidence suggests that peripheral monocyte activation represents one of the initial steps in the establishment of the HIV reservoir in the brain. However, it is unclear whether peripheral monocyte activation is more modifiable with certain antiretroviral medications. This study will examine whether subjects with HAND randomized to zidovudine, which has demonstrated antiretroviral activity within monocytes, have less peripheral monocyte activation. If the proposed study indicates that HAND severity is related to peripheral immune activation and that the beneficial effect of certain antiretroviral agents may be related to modification of immune activation, this would lead to future studies of therapies that directly target immune activation for the amelioration of HAND or as a means to interrupt the establishment of the HIV reservoir in the brain, which represents one of the barriers to HIV eradication. The principal investigator for this proposal has assembled a diverse mentoring team with experts from HIV clinical research, neurosciences, and HIV basic research. These mentors each bring important strengths to the multidisciplinary research plan and have agreed to meet regularly with the principal investigator in order to provide guidance in research and career development. The principal investigator has significant experience in HIV clinical care and research. In addition to his medical degree, he holds a masters degree in health sciences research. He is based at one of the largest centers for HIV care in the United States. As part of the research proposal, he will also receive formal coursework in neuro-HIV/AIDS research, clinical trials, neuropsychology, biostatistics, and the responsible conduct of research. He will regularly attend international HIV research meetings in which he will present his research. Overall, this career development project will allow the principal investigator to pursue the goal o becoming an established investigator and leader in HIV CNS research.

描述（由申请人提供）：此拟议的K-23补助金重新提交将提供初级首席研究员的职业发展，其目标是成为人类免疫缺陷病毒（HIV）临床研究的领导者，重点是中枢神经系统（CNS）参与HIV。HIV的CNS并发症仍然是发病率和死亡率的主要来源。HIV相关神经认知障碍（HAND）的患病率正在增加。HAND的存在是导致工作残疾、生活质量差和死亡的危险因素。拟议的研究计划涉及HIV中枢神经系统（CNS）研究的三个最重要领域：某些抗逆转录病毒药物对HAND认知改善的差异影响的可能性，特定脑脊液（CSF）的作用， 生物标志物作为HAND活性的指标，以及单核细胞和淋巴细胞活化在HIV神经发病机制中的不完全确定的作用。拟议的研究与NIMH任务高度相关，其中包括开发新的治疗方法以减轻HIV的CNS并发症。这项研究将在一个城市艾滋病中心进行，那里的许多病人由于贫困和缺乏医疗保险而资源有限。齐多夫定是一种抗逆转录病毒药物，目前在美国以通用形式存在，是穿透CNS最有效的抗逆转录病毒药物之一，并且是历史上研究最好的HIV相关痴呆症抗逆转录病毒药物。研究者的主要假设是，在48周的过程中，在抗逆转录病毒初治的HAND受试者中加入齐多夫定将导致显著更大的神经认知改善和生物标志物。这将在一项小型临床研究中进行测试，受试者将接受标准的抗逆转录病毒治疗方案加齐多夫定或安慰剂。如果研究显示随机接受齐多夫定治疗的受试者在神经认知和/或生物标志物方面有上级改善，研究小组将继续进行更大规模的研究，对HAND患者进行齐多夫定治疗。该提案的次要目的涉及以下假设：生物标志物是HAND的反映，细胞因子和外周免疫激活独立地促成HAND，并且可能是未来治疗的修饰靶点。该研究小组的目标是根据已建立的大型样本库来估计正常的CSF生物标志物值。他们已经表明，某些生物标志物与HAND严重程度相关，并在治疗期间得到改善。一个目标是测试八种生物标志物的综合评分以及标准化的神经心理学测试。如果证明了有希望的相关性，则将在更大的研究中测试生物标志物评分作为HAND的相关性。研究小组在以前的工作中也证明了CSF IFN-α水平与HAND受试者的神经心理学评分呈负相关。他们还表明，在HIV脑炎的小鼠模型中，IFN-α阻断治疗与工作记忆的益处和大脑中病理标记物的减少有关。拟议的临床研究将使该团队能够在这些发现的基础上再接再厉。研究小组假设，尽管进行了有效的抗逆转录病毒治疗，但仍有残余神经认知障碍的个体将具有较高的残余CSF IFN-α水平。这将为研究小组为HAND患者开发的IFN-α修饰疗法的临床研究奠定基础。另一个次要目的是研究外周血单核细胞和淋巴细胞活化在HAND中的作用。很明显，外周淋巴细胞活化有助于整个艾滋病发病机制。然而，目前尚不清楚淋巴细胞活化是否独立地导致HAND。目前的证据表明，外周单核细胞活化是在大脑中建立HIV储库的初始步骤之一。然而，目前还不清楚外周血单核细胞活化是否更容易被某些抗逆转录病毒药物改变。本研究将检查随机分配至齐多夫定组的HAND受试者是否具有较少的外周血单核细胞活化，齐多夫定在单核细胞内具有抗逆转录病毒活性。如果拟议的研究表明HAND的严重程度与外周免疫激活有关，并且某些抗逆转录病毒药物的有益作用可能与免疫激活的改变有关，这将导致未来研究直接针对免疫激活的疗法以改善HAND或作为中断大脑中HIV储存库建立的手段，这是根除艾滋病的障碍之一。该提案的主要研究者组建了一个由来自艾滋病毒临床研究、神经科学和艾滋病毒基础研究的专家组成的多元化指导团队。这些导师都为多学科研究计划带来了重要的优势，并同意定期与首席研究员会面，以提供研究和职业发展方面的指导。主要研究者在艾滋病毒临床护理和研究方面具有丰富的经验。除了医学学位外，他还拥有健康科学研究硕士学位。他在美国最大的艾滋病护理中心工作。作为研究计划的一部分，他还将接受神经艾滋病毒/艾滋病研究，临床试验，神经心理学，生物统计学和负责任的研究行为的正式课程。他将定期参加国际艾滋病毒研究会议，并在会上介绍他的研究。总的来说，这个职业发展项目将使主要研究者追求成为HIV CNS研究的既定研究者和领导者的目标。